A Single Nucleotide Polymorphism in Human APOBEC3C Enhances Restriction of Lentiviruses.

Cristina J Wittkopp,Linda Chelico,Michael Emerman,Madison B Adolph,Lily I Wu,Susan R Ross

doi:10.1371/journal.ppat.1005865

Cristina J Wittkopp, Linda Chelico + Show 4 more

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https://doi.org/10.1371/journal.ppat.1005865

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Abstract

Humans express seven human APOBEC3 proteins, which can inhibit viruses and endogenous retroelements through cytidine deaminase activity. The seven paralogs differ in the potency of their antiviral effects, as well as in their antiviral targets. One APOBEC3, APOBEC3C, is exceptional as it has been found to only weakly block viruses and endogenous retroelements compared to other APOBEC3s. However, our positive selection analyses suggest that APOBEC3C has played a role in pathogen defense during primate evolution. Here, we describe a single nucleotide polymorphism in human APOBEC3C, a change from serine to isoleucine at position 188 (I188) that confers potent antiviral activity against HIV-1. The gain-of-function APOBEC3C SNP results in increased enzymatic activity and hypermutation of target sequences when tested in vitro, and correlates with increased dimerization of the protein. The I188 is widely distributed in human African populations, and is the ancestral primate allele, but is not found in chimpanzees or gorillas. Thus, while other hominids have lost activity of this antiviral gene, it has been maintained, or re-acquired, as a more active antiviral gene in a subset of humans. Taken together, our results suggest that APOBEC3C is in fact involved in protecting hosts from lentiviruses.

Highlights

The APOBEC3 locus encodes seven cytidine deaminase proteins that inhibit endogenous retroelements, lentiviruses such as HIV-1, and other viruses [1]
The human APOBEC3 gene family consists of seven cytidine deaminases that mutate viral genomes
We report that most humans express a version of APOBEC3C that only weakly blocks HIV, there is a polymorphism found in African populations that drastically enhances its anti-HIV activity

Summary

Introduction

The APOBEC3 locus encodes seven cytidine deaminase proteins that inhibit endogenous retroelements, lentiviruses such as HIV-1, and other viruses [1]. In order for APOBEC3 proteins to restrict lentiviruses such as HIV-1, they are packaged into virions, brought to a target cell, and deaminate cytidines on ssDNA during reverse transcription, resulting in cytidine to uracil mutations in the viral genome. Lentiviruses, in turn, select for Vif alleles that target these APOBEC3 variants, leading to further adaptive evolution of APOBEC3 genes through selection for mutations that allow that host to evade viral infections. APOBEC3 genes involved in blocking viral replication are expected to exhibit signatures of positive selection. APOBEC3s involved in lentiviral restriction should have signatures of positive selection at the Vif:APOBEC3 interface [4]

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